Formulations of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione

ABSTRACT

Pharmaceutical compositions and single unit dosage forms of 4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione, or a pharmaceutically acceptable stereoisomer, prodrug, salt, solvate, hydrate, or clathrate, are provided herein. Also provided are methods of treating, managing, or preventing various disorders, such as cancer or an inflammatory disease.

This application is a continuation of U.S. patent application Ser. No.14/447,450, filed Jul. 30, 2014, which is a continuation of U.S. patentapplication Ser. No. 12/783,390, filed May 19, 2010, now U.S. Pat. No.8,828,427, which claims priority to U.S. Provisional Application No.61/179,678, filed May 19, 2009, each of which are incorporated herein byreference in their entireties.

1. FIELD

Provided herein are formulations and dosage forms of pomolidomide, i.e.,4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione or CC-4047.Methods of using the formulations and dosage forms are also providedherein.

2. BACKGROUND

Drug substances are usually administered as part of a formulation incombination with one or more other agents that serve varied andspecialized pharmaceutical functions. Dosage forms of various types maybe made through selective use of pharmaceutical excipients. Aspharmaceutical excipients have various functions and contribute to thepharmaceutical formulations in many different ways, e.g.,solubilization, dilution, thickening, stabilization, preservation,coloring, flavoring, etc. The properties that are commonly consideredwhen formulating an active drug substance include bioavailability, easeof manufacture, ease of administration, and stability of the dosageform. Due to the varying properties of the active drug substance to beformulated, dosage forms typically require pharmaceutical excipientsthat are uniquely tailored to the active drug substance in order toachieve advantageous physical and pharmaceutical properties.

Pomolidomide, which is also known as CC-4047, is chemically named4-amino-2-(2,6-dioxopiperidine-3-yl)isoindoline-1,3-dione. Pomolidomideis an immunomodulatory compound that inhibits, for example, LPS inducedmonocyte TNFα, IL-1β, IL-12, IL-6, MIP-1, MCP-1, GM-CSF, G-CSF, andCOX-2 production. The compound is also known to co-stimulate theactivation of T-cells. Pomolidomide and method of synthesizing thecompound are described, e.g., in U.S. Pat. No. 5,635,517, the entiretyof which is incorporated herein by reference.

Due to its diversified pharmacological properties, pomolidomide isuseful in treating, preventing, and/or managing various diseases ordisorders. Thus, a need exists as to dosage forms of pomolidomide havingadvantageous physical and pharmaceutical properties.

3. SUMMARY

Provided herein are pharmaceutical dosage forms of pomolidomide, or apharmaceutically acceptable stereoisomer, prodrug, salt, solvate,hydrate, or clathrate thereof. Also provided herein are methods oftreating, managing, or preventing diseases and conditions such as, butnot limited to, cancer, pain, Macular Degeneration, a skin disease, apulmonary disorder, an asbestos-related disorder, a parasitic disease,an immunodeficiency disorder, a CNS disorder, CNS injury,atherosclerosis, a sleep disorder, hemoglobinopathy, anemia, aninflammatory disease, an autoimmune disease, a viral disease, a geneticdisease, an allergic disease, a bacterial disease, an ocular neovasculardisease, a choroidal neovascular disease, a retina neovascular disease,and rubeosis, using pomolidomide, or a pharmaceutically acceptablestereoisomer, prodrug, salt, solvate, hydrate, or clathrate thereof, inthe dosage forms described herein.

3.1. Definitions

As used herein and unless otherwise indicated, a composition that is“substantially free” of a compound means that the composition containsless than about 20 percent by weight, more preferably less than about 10percent by weight, even more preferably less than about 5 percent byweight, and most preferably less than about 3 percent by weight of thecompound.

As used herein and unless otherwise indicated, the term “stereomericallypure” means a composition that comprises one stereoisomer of a compoundand is substantially free of other stereoisomers of that compound. Forexample, a stereomerically pure composition of a compound having onechiral center will be substantially free of the opposite enantiomer ofthe compound. A stereomerically pure composition of a compound havingtwo chiral centers will be substantially free of other diastereomers ofthe compound. A typical stereomerically pure compound comprises greaterthan about 80 percent by weight of one stereoisomer of the compound andless than about 20 percent by weight of other stereoisomers of thecompound, more preferably greater than about 90 percent by weight of onestereoisomer of the compound and less than about 10 percent by weight ofthe other stereoisomers of the compound, even more preferably greaterthan about 95 percent by weight of one stereoisomer of the compound andless than about 5 percent by weight of the other stereoisomers of thecompound, and most preferably greater than about 97 percent by weight ofone stereoisomer of the compound and less than about 3 percent by weightof the other stereoisomers of the compound.

As used herein and unless otherwise indicated, the term“enantiomerically pure” means a stereomerically pure composition of acompound having one chiral center.

As used herein, unless otherwise specified, the term “pharmaceuticallyacceptable salt(s),” as used herein includes, but is not limited to,salts of acidic or basic moieties of thalidomide. Basic moieties arecapable of forming a wide variety of salts with various inorganic andorganic acids. The acids that can be used to prepare pharmaceuticallyacceptable acid addition salts of such basic compounds are those thatform non-toxic acid addition salts, i.e., salts containingpharmacologically acceptable anions. Suitable organic acids include, butare not limited to, maleic, fumaric, benzoic, ascorbic, succinic,acetic, formic, oxalic, propionic, tartaric, salicylic, citric,gluconic, lactic, mandelic, cinnamic, oleic, tannic, aspartic, stearic,palmitic, glycolic, glutamic, gluconic, glucaronic, saccharic,isonicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic,benzenesulfonic acids, or pamoic (i.e.,1,1′-methylene-bis-(2-hydroxy-3-naphthoate) acids. Suitable inorganicacids include, but are not limited to, hydrochloric, hydrobromic,hydroiodic, sulfuric, phosphoric, or nitric acids. Compounds thatinclude an amine moiety can form pharmaceutically acceptable salts withvarious amino acids, in addition to the acids mentioned above. Chemicalmoieties that are acidic in nature are capable of forming base saltswith various pharmacologically acceptable cations. Examples of suchsalts are alkali metal or alkaline earth metal salts and, particularly,calcium, magnesium, sodium, lithium, zinc, potassium, or iron salts.

As used herein, and unless otherwise specified, the term “solvate” meansa compound provided herein or a salt thereof, that further includes astoichiometric or non-stoichiometric amount of solvent bound bynon-covalent intermolecular forces. Where the solvent is water, thesolvate is a hydrate.

As used herein and unless otherwise indicated, the term “prodrug” meansa derivative of a compound that can hydrolyze, oxidize, or otherwisereact under biological conditions (in vitro or in vivo) to provide thecompound. Examples of prodrugs include, but are not limited to,derivatives of thalidomide that include biohydrolyzable moieties such asbiohydrolyzable amides, biohydrolyzable esters, biohydrolyzablecarbamates, biohydrolyzable carbonates, biohydrolyzable ureides, andbiohydrolyzable phosphate analogues. Other examples of prodrugs includederivatives of thalidomide that include —NO, —NO₂, —ONO, or —ONO₂moieties.

As used herein and unless otherwise indicated, the terms“biohydrolyzable carbamate,” “biohydrolyzable carbonate,”“biohydrolyzable ureide,” “biohydrolyzable phosphate” mean a carbamate,carbonate, ureide, or phosphate, respectively, of a compound thateither: 1) does not interfere with the biological activity of thecompound but can confer upon that compound advantageous properties invivo, such as uptake, duration of action, or onset of action; or 2) isbiologically inactive but is converted in vivo to the biologicallyactive compound. Examples of biohydrolyzable carbamates include, but arenot limited to, lower alkylamines, substituted ethylenediamines,aminoacids, hydroxyalkylamines, heterocyclic and heteroaromatic amines,and polyether amines.

As used herein and unless otherwise indicated, the term “biohydrolyzableester” means an ester of a compound that either: 1) does not interferewith the biological activity of the compound but can confer upon thatcompound advantageous properties in vivo, such as uptake, duration ofaction, or onset of action; or 2) is biologically inactive but isconverted in vivo to the biologically active compound. Examples ofbiohydrolyzable esters include, but are not limited to, lower alkylesters, alkoxyacyloxy esters, alkyl acylamino alkyl esters, and cholineesters.

As used herein and unless otherwise indicated, the term “biohydrolyzableamide” means an amide of a compound that either: 1) does not interferewith the biological activity of the compound but can confer upon thatcompound advantageous properties in vivo, such as uptake, duration ofaction, or onset of action; or 2) is biologically inactive but isconverted in vivo to the biologically active compound. Examples ofbiohydrolyzable amides include, but are not limited to, lower alkylamides, α-amino acid amides, alkoxyacyl amides, andalkylaminoalkylcarbonyl amides.

As used herein, and unless otherwise specified, the terms “treat,”“treating” and “treatment” contemplate an action that occurs while apatient is suffering from the specified disease or disorder, whichreduces the severity of the disease or disorder, or retards or slows theprogression of the disease or disorder.

As used herein, and unless otherwise specified, the terms “prevent,”“preventing” and “prevention” refer to the prevention of the onset,recurrence or spread of a disease or disorder, or of one or moresymptoms thereof. The terms “prevent,” “preventing” and “prevention”contemplate an action that occurs before a patient begins to suffer fromthe specified disease or disorder, which inhibits or reduces theseverity of the disease or disorder.

As used herein, and unless otherwise indicated, the terms “manage,”“managing” and “management” encompass preventing the recurrence of thespecified disease or disorder in a patient who has already suffered fromthe disease or disorder, and/or lengthening the time that a patient whohas suffered from the disease or disorder remains in remission. Theterms encompass modulating the threshold, development and/or duration ofthe disease or disorder, or changing the way that a patient responds tothe disease or disorder.

As used herein, and unless otherwise specified, the term “about,” whenused in connection with doses, amounts, or weight percent of ingredientsof a composition or a dosage form, means dose, amount, or weight percentthat is recognized by those of ordinary skill in the art to provide apharmacological effect equivalent to that obtained from the specifieddose, amount, or weight percent is encompassed. Specifically, the term“about” contemplates a dose, amount, or weight percent within 30%, 25%,20%, 15%, 10%, or 5% of the specified dose, amount, or weight percent isencompassed.

As used herein, and unless otherwise specified, the term “stable,” whenused in connection with a formulation or a dosage form, means that theactive ingredient of the formulation or dosage form remains solubilizedfor a specified amount of time and does not significantly degrade oraggregate or become otherwise modified (e.g., as determined, forexample, by HPLC). In some embodiments, about 70 percent or greater,about 80 percent or greater or about 90 percent or greater of thecompound remains solubilized after the specified period.

4. DETAILED DESCRIPTION

Provided herein are pharmaceutical dosage forms of pomolidomide, or apharmaceutically acceptable stereoisomer, prodrug, salt, solvate,hydrate, or clathrate thereof. In some embodiments, the dosage forms aresuitable for oral administration to a patient. In other embodiments, thedosage forms provided herein exhibit advantageous physical and/orpharmacological properties. Such properties include, but are not limitedto, ease of assay, content uniformity, flow properties for manufacture,dissolution and bioavailability, and stability. In certain embodiments,the dosage forms provided herein have a shelf life of at least about 12months, at least about 24 months, or at least about 36 months withoutrefrigeration.

Also provided herein are kits comprising pharmaceutical compositions anddosage forms provided herein. Also provided herein are methods oftreating, managing, and/or preventing a disease or condition, whichcomprises administering to a patient in need thereof a pharmaceuticalcomposition or a dosage form provided herein.

4.1 Compositions and Dosage Forms

In one embodiment, provided herein is a single unit dosage form suitablefor oral administration to a human comprising: an amount equal to orgreater than about 1, 5, 10, 15, 20, 25, 30, 50, 75, 100, 150, or 200 mgof an active ingredient; and a pharmaceutically acceptable excipient;wherein the active ingredient is pomolidomide, or a pharmaceuticallyacceptable stereoisomer, prodrug, salt, solvate, or clathrate thereof.In some embodiments, the amount of active ingredient is from about 0.1to about 100 mg, from about 0.5 to about 50 mg, from, about 0.5 to about25 mg, from about 1 mg to about 10 mg, from about 0.5 to about 5 mg, orfrom about 1 mg to about 5 mg. In one embodiment, the amount of theactive ingredient is about 0.5 mg. In another embodiment, the amount ofthe active ingredient is about 1 mg. In another embodiment, the amountof the active ingredient is about 2 mg. In another embodiment, theamount of the active ingredient is about 5 mg.

Pharmaceutical compositions and formulations provided herein can bepresented as discrete dosage forms, such as capsules (e.g., gelcaps),caplets, tablets, troches, lozenges, dispersions, and suppositories eachcontaining a predetermined amount of an active ingredient as a powder orin granules, a solution, or a suspension in an aqueous or non-aqueousliquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion.Because of their ease of administration, tablets, caplets, and capsulesrepresent a preferred oral dosage unit forms.

Tablets, caplets, and capsules typically contain from about 50 mg toabout 500 mg of the pharmaceutical composition (i.e., active ingredientand excipient(s)). Capsules can be of any size. Examples of standardsizes include #000, #00, #0, #1, #2, #3, #4, and #5. See, e.g.,Remington's Pharmaceutical Sciences, page 1658-1659 (Alfonso Gennaroed., Mack Publishing Company, Easton Pa., 18th ed., 1990), which isincorporated by reference. In some embodiments, capsules provided hereinare of size #1 or larger, #2 or larger, or #4 or larger.

Also provided herein are anhydrous pharmaceutical compositions anddosage forms including an active ingredient, since water can facilitatethe degradation of some compounds. For example, the addition of water(e.g., 5 percent) is widely accepted in the pharmaceutical arts as ameans of simulating shelf-life, i.e., long-term storage in order todetermine characteristics such as shelf-life or the stability offormulations over time. See, e.g., Jens T. Carstensen, Drug Stability:Principles & Practice, 2d. Ed., Marcel Dekker, NY, N.Y., 1995, pp.379-80. In effect, water and heat accelerate decomposition. Thus, theeffect of water on a formulation can be of great significance sincemoisture and/or humidity are commonly encountered during manufacture,handling, packaging, storage, shipment, and use of formulations.

An anhydrous pharmaceutical compositions should be prepared and storedsuch that the anhydrous nature is maintained. Accordingly, in someembodiments, anhydrous compositions are packaged using materials knownto prevent exposure to water such that they can be included in suitableformulary kits. Examples of suitable packaging include, but are notlimited to, hermetically sealed foils, plastic or the like, unit dosecontainers, blister packs, and strip packs.

In this regard, also provided herein is a method of preparing a solidpharmaceutical formulation including an active ingredient throughadmixing the active ingredient and an excipient under anhydrous or lowmoisture/humidity conditions, wherein the ingredients are substantiallyfree of water. The method can further include packaging the anhydrous ornon-hygroscopic solid formulation under low moisture conditions. Byusing such conditions, the risk of contact with water is reduced and thedegradation of the active ingredient can be prevented or substantiallyreduced.

Also provided herein are lactose-free pharmaceutical compositions anddosage forms. Compositions and dosage forms that comprise an activeingredient that is a primary or secondary amine are preferablylactose-free. As used herein, the term “lactose-free” means that theamount of lactose present, if any, is insufficient to substantiallyincrease the degradation rate of an active ingredient that is a primaryor secondary amine. Lactose-free compositions provided herein cancomprise excipients which are well known in the art and are listed inthe USP (XXI)/NF (XVI), which is incorporated herein by reference.

In one embodiment, pomolidomide, or a pharmaceutically acceptablestereoisomer, prodrug, salt, solvate, or clathrate thereof, comprisesfrom about 0.1 to about 10 weight percent of total weight of thecomposition. In another embodiment, pomolidomide, or a pharmaceuticallyacceptable stereoisomer, prodrug, salt, solvate, or clathrate thereof,comprises from about 0.1 to about 5 weight percent of total weight ofthe composition. In another embodiment, pomolidomide, or apharmaceutically acceptable stereoisomer, prodrug, salt, solvate, orclathrate thereof, comprises from about 0.1 to about 3 weight percent oftotal weight of the composition. In another embodiment, pomolidomide, ora pharmaceutically acceptable stereoisomer, prodrug, salt, solvate, orclathrate thereof, comprises from about 0.5 to about 3 weight percent oftotal weight of the composition. In another embodiment, pomolidomide, ora pharmaceutically acceptable stereoisomer, prodrug, salt, solvate, orclathrate thereof, comprises from about 0.5 to about 2 weight percent oftotal weight of the composition. In another embodiment, pomolidomide, ora pharmaceutically acceptable stereoisomer, prodrug, salt, solvate, orclathrate thereof, comprises about 1 weight percent of total weight ofthe composition. In another embodiment, pomolidomide, or apharmaceutically acceptable stereoisomer, prodrug, salt, solvate, orclathrate thereof, comprises about 0.8 weight percent of total weight ofthe composition. In another embodiment, pomolidomide, or apharmaceutically acceptable stereoisomer, prodrug, salt, solvate, orclathrate thereof, comprises about 2 weight percent of total weight ofthe composition. In another embodiment, pomolidomide, or apharmaceutically acceptable stereoisomer, prodrug, salt, solvate, orclathrate thereof, comprises about 1.7 weight percent of total weight ofthe composition.

In one embodiment, the active ingredient and carrier, diluent, binder,or filler are directly blended as described herein elsewhere. In anotherembodiment, the carrier, diluent, binder, or filler comprises mannitoland/or starch. In one embodiment, the mannitol is spray dried mannitol.In another embodiment, the starch is pregelatinized starch.

In one embodiment, the carrier, diluent, binder, or filler comprisesfrom about 70 to about 99 weight percent of total weight of thecomposition. In another embodiment, the carrier, diluent, binder, orfiller comprises from about 80 to about 99 weight percent of totalweight of the composition. In another embodiment, the carrier, diluent,binder, or filler comprises from about 85 to about 99 weight percent oftotal weight of the composition. In another embodiment, the carrier,diluent, binder, or filler comprises from about 90 to about 99 weightpercent of total weight of the composition. In another embodiment, thecarrier, diluent, binder, or filler comprises from about 95 to about 99weight percent of total weight of the composition. In anotherembodiment, the carrier, diluent, binder, or filler comprises about 98weight percent of total weight of the composition. In anotherembodiment, the carrier, diluent, binder, or filler comprises about 99weight percent of total weight of the composition.

In one embodiment, the dosage forms provided herein comprise bothmannitol and starch. In one embodiment, mannitol and starch comprisefrom about 70 to about 99 weight percent of total weight of thecomposition. In another embodiment, mannitol and starch comprise fromabout 80 to about 99 weight percent of total weight of the composition.In another embodiment, mannitol and starch comprise from about 85 toabout 99 weight percent of total weight of the composition. In anotherembodiment, mannitol and starch comprise from about 90 to about 99weight percent of total weight of the composition. In anotherembodiment, mannitol and starch comprise from about 95 to about 99weight percent of total weight of the composition. In anotherembodiment, mannitol and starch comprise about 98 weight percent oftotal weight of the composition. In another embodiment, mannitol andstarch comprise about 99 weight percent of total weight of thecomposition.

In one embodiment, the ratio of mannitol:starch in the dosage form isfrom about 1:1 to about 1:1.5. In one embodiment, the ratio ofmannitol:starch in the dosage form is about 1:1.3.

In another embodiment, the dosage form comprises a lubricant. In oneembodiment, the dosage form comprises about 0.2, 0.3, 0.5, 0.6, or 0.8mg of lubricant. In another embodiment, the dosage form comprises about0.16, 0.32, 0.64, or 0.75 mg of lubricant. In one embodiment, thelubricant is sodium stearyl fumarate (PRUV).

In one embodiment, the lubricant, e.g., PRUV, comprises from about 0.01to about 5 weight percent of total weight of the composition. In anotherembodiment, the lubricant, e.g., PRUV, comprises from about 0.01 toabout 1 weight percent of total weight of the composition. In anotherembodiment, the lubricant, e.g., PRUV, comprises from about 0.1 to about1 weight percent of total weight of the composition. In anotherembodiment, the lubricant, e.g., PRUV, comprises from about 0.1 to about0.5 weight percent of total weight of the composition. In anotherembodiment, the lubricant, e.g., PRUV, comprises from about 0.2 to about0.3 weight percent of total weight of the composition. In anotherembodiment, the lubricant, e.g., PRUV, comprises about 0.25 weightpercent of total weight of the composition.

In some embodiments, because it is typical to obtain pomolidomide, or apharmaceutically acceptable stereoisomer, prodrug, salt, solvate, orclathrate thereof, at a purity of less than 100%, the formulations anddosage forms provided herein may be defined as compositions,formulations, or dosage forms that comprise pomolidomide, or apharmaceutically acceptable stereoisomer, prodrug, salt, solvate, orclathrate thereof, at an amount that provides the potency of a specifiedamount of 100% pure pomolidomide.

For example, in one embodiment, provided herein is a single unit dosageform comprising: 1) pomolidomide, or a pharmaceutically acceptablestereoisomer, prodrug, salt, solvate, or clathrate thereof, present atan amount that provides about 0.5, 1, 2, 3, 4, or 5 mg potency ofpomolidomide; and 2) about 60, 120, 250, 180, 240, or 300 mg of acarrier, diluent, binder, or filler, respectively. In one embodiment,the amount of a carrier, diluent, binder, or filler is about 62, 124,248, 177, 236, or 295 mg, respectively.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 0.5 mg potency of pomolidomide; and 2) a pharmaceuticallyacceptable excipient. In one embodiment, the total weight of the dosageform is about 62.5 mg. In one embodiment, the dosage form is suitablefor administration in a size 4 or larger capsule. In one embodiment, theexcipient comprises a carrier, diluent, binder, or filler. In oneembodiment, the excipients comprise a carrier, diluent, binder, orfiller and a lubricant.

In one embodiment where the total weight of the dosage form is about62.5 mg, the carrier, diluent, binder, or filler comprises mannitoland/or starch. In one embodiment, the excipient comprises both mannitoland starch. In one embodiment, where both mannitol and starch arepresent in the dosage form, the dosage form comprises about 35 mg ofstarch, and the remaining weight is filled by starch. In one embodiment,the mannitol is spray dried mannitol. In another embodiment, the starchis pregelatinized starch.

In one embodiment where the total weight of the dosage form is about62.5 mg and where a lubricant is present, the lubricant is sodiumstearyl fumarate. In one embodiment, the sodium stearyl fumarate ispresent at an amount of about 0.2 mg. In one embodiment, the sodiumstearyl fumarate is present at an amount of about 0.16 mg.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 0.5 mg potency of pomolidomide; 2) about 35 mg of pregelatinizedstarch; 3) about 0.16 mg of sodium stearyl fumarate; and 4) spray driedmannitol at an amount that brings the total weight of the dosage form to62.5 mg. In one embodiment, the dosage form is suitable foradministration in a size 4 or larger capsule.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 1 mg potency of pomolidomide; and 2) a pharmaceutically acceptableexcipient. In one embodiment, the total weight of the dosage form isabout 125 mg. In one embodiment, the dosage form is suitable foradministration in a size 4 or larger capsule. In one embodiment, theexcipient comprises a carrier, diluent, binder, or filler. In oneembodiment, the excipients comprise a carrier, diluent, binder, orfiller and a lubricant.

In one embodiment where the total weight of the dosage form is about 125mg, the carrier, diluent, binder, or filler comprises mannitol and/orstarch. In one embodiment, the excipient comprises both mannitol andstarch. In one embodiment, where both mannitol and starch are present inthe dosage form, the dosage form comprises about 70 mg of starch, andthe remaining weight is filled by starch. In one embodiment, themannitol is spray dried mannitol. In another embodiment, the starch ispregelatinized starch.

In one embodiment where the total weight of the dosage form is about 125mg and where a lubricant is present, the lubricant is sodium stearylfumarate. In one embodiment, the sodium stearyl fumarate is present atan amount of about 0.3 mg. In one embodiment, the sodium stearylfumarate is present at an amount of about 0.32 mg.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 1 mg potency of pomolidomide; 2) about 70 mg of pregelatinizedstarch; 3) about 0.32 mg of sodium stearyl fumarate; and 4) spray driedmannitol at an amount that brings the total weight of the dosage form to125 mg. In one embodiment, the dosage form is suitable foradministration in a size 4 or larger capsule.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 2 mg potency of pomolidomide; and 2) a pharmaceutically acceptableexcipient. In one embodiment, the total weight of the dosage form isabout 250 mg. In one embodiment, the dosage form is suitable foradministration in a size 2 or larger capsule. In one embodiment, theexcipient comprises a carrier, diluent, binder, or filler. In oneembodiment, the excipients comprise a carrier, diluent, binder, orfiller and a lubricant.

In one embodiment where the total weight of the dosage form is about 250mg, the carrier, diluent, binder, or filler comprises mannitol and/orstarch. In one embodiment, the excipient comprises both mannitol andstarch. In one embodiment, where both mannitol and starch are present inthe dosage form, the dosage form comprises about 140 mg of starch, andthe remaining weight is filled by starch. In one embodiment, themannitol is spray dried mannitol. In another embodiment, the starch ispregelatinized starch.

In one embodiment where the total weight of the dosage form is about 250mg and where a lubricant is present, the lubricant is sodium stearylfumarate. In one embodiment, the sodium stearyl fumarate is present atan amount of about 0.6 mg. In one embodiment, the sodium stearylfumarate is present at an amount of about 0.64 mg.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 2 mg potency of pomolidomide; 2) about 140 mg of pregelatinizedstarch; 3) about 0.64 mg of sodium stearyl fumarate; and 4) spray driedmannitol at an amount that brings the total weight of the dosage form to250 mg. In one embodiment, the dosage form is suitable foradministration in a size 2 or larger capsule.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 3 mg potency of pomolidomide; and 2) a pharmaceutically acceptableexcipient. In one embodiment, the total weight of the dosage form isabout 180 mg. In one embodiment, the dosage form is suitable foradministration in a size 2 or larger capsule. In one embodiment, theexcipient comprises a carrier, diluent, binder, or filler. In oneembodiment, the excipients comprise a carrier, diluent, binder, orfiller and a lubricant.

In one embodiment where the total weight of the dosage form is about 180mg, the carrier, diluent, binder, or filler comprises mannitol and/orstarch. In one embodiment, the excipient comprises both mannitol andstarch. In one embodiment, where both mannitol and starch are present inthe dosage form, the dosage form comprises about 100 mg of starch, andthe remaining weight is filled by starch. In one embodiment, themannitol is spray dried mannitol. In another embodiment, the starch ispregelatinized starch.

In one embodiment where the total weight of the dosage form is about 180mg and where a lubricant is present, the lubricant is sodium stearylfumarate. In one embodiment, the sodium stearyl fumarate is present atan amount of about 0.5 mg. In one embodiment, the sodium stearylfumarate is present at an amount of about 0.45 mg.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 3 mg potency of pomolidomide; 2) about 100.8 mg of pregelatinizedstarch; 3) about 0.45 mg of sodium stearyl fumarate; and 4) spray driedmannitol at an amount that brings the total weight of the dosage form to180 mg. In one embodiment, the dosage form is suitable foradministration in a size 2 or larger capsule.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 4 mg potency of pomolidomide; and 2) a pharmaceutically acceptableexcipient. In one embodiment, the total weight of the dosage form isabout 240 mg. In one embodiment, the dosage form is suitable foradministration in a size 2 or larger capsule. In one embodiment, theexcipient comprises a carrier, diluent, binder, or filler. In oneembodiment, the excipients comprise a carrier, diluent, binder, orfiller and a lubricant.

In one embodiment where the total weight of the dosage form is about 240mg, the carrier, diluent, binder, or filler comprises mannitol and/orstarch. In one embodiment, the excipient comprises both mannitol andstarch. In one embodiment, where both mannitol and starch are present inthe dosage form, the dosage form comprises about 135 mg of starch, andthe remaining weight is filled by starch. In one embodiment, themannitol is spray dried mannitol. In another embodiment, the starch ispregelatinized starch.

In one embodiment where the total weight of the dosage form is about 240mg and where a lubricant is present, the lubricant is sodium stearylfumarate. In one embodiment, the sodium stearyl fumarate is present atan amount of about 0.6 mg.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 4 mg potency of pomolidomide; 2) about 134.4 mg of pregelatinizedstarch; 3) about 0.6 mg of sodium stearyl fumarate; and 4) spray driedmannitol at an amount that brings the total weight of the dosage form to240 mg. In one embodiment, the dosage form is suitable foradministration in a size 2 or larger capsule.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 5 mg potency of pomolidomide; and 2) a pharmaceutically acceptableexcipient. In one embodiment, the total weight of the dosage form isabout 300 mg. In one embodiment, the dosage form is suitable foradministration in a size 1 or larger capsule. In one embodiment, theexcipient comprises a carrier, diluent, binder, or filler. In oneembodiment, the excipients comprise a carrier, diluent, binder, orfiller and a lubricant.

In one embodiment where the total weight of the dosage form is about 300mg, the carrier, diluent, binder, or filler comprises mannitol and/orstarch. In one embodiment, the excipient comprises both mannitol andstarch. In one embodiment, where both mannitol and starch are present inthe dosage form, the dosage form comprises about 168 mg of starch, andthe remaining weight is filled by starch. In one embodiment, themannitol is spray dried mannitol. In another embodiment, the starch ispregelatinized starch.

In one embodiment where the total weight of the dosage form is about 300mg and where a lubricant is present, the lubricant is sodium stearylfumarate. In one embodiment, the sodium stearyl fumarate is present atan amount of about 0.8 mg. In one embodiment, the sodium stearylfumarate is present at an amount of about 0.75 mg.

In one embodiment, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 5 mg potency of pomolidomide; 2) about 168 mg of pregelatinizedstarch; 3) about 0.75 mg of sodium stearyl fumarate; and 4) spray driedmannitol at an amount that brings the total weight of the dosage form to300 mg. In one embodiment, the dosage form is suitable foradministration in a size 1 or larger capsule.

In another embodiment, provided herein is a dosage form comprisingpomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 0.5 mg potency of pomolidomide, which is stable for a period of atleast about 12, about 24, or about 36 months without refrigeration. Insome embodiments, the dosage form comprises mannitol and/or starch. Inone embodiment where both starch and mannitol are present in the dosageform, starch is present at an amount of about 35 mg, and mannitol ispresent at an amount that brings the total weight of composition toabout 62.5 mg. In some embodiments, the dosage form further comprisessodium stearyl fumarate at an amount of about 0.2 mg or about 0.16 mg.In some embodiments, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 0.5 mg potency of pomolidomide, about 35 mg pregelatinized starch;about 0.16 mg sodium stearyl fumarate; and spray dried mannitol at anamount that brings the total weight of the dosage form to 62.5 mg;wherein the dosage form is stable for a period of at least about 12,about 24, or about 36 months without refrigeration. In one embodiment,the dosage form is suitable for administration in a size 4 or largercapsule.

In another embodiment, provided herein is a dosage form comprisingpomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 1 mg potency of pomolidomide, which is stable for a period of atleast about 12, about 24, or about 36 months without refrigeration. Insome embodiments, the dosage form comprises mannitol and/or starch. Inone embodiment where both starch and mannitol are present in the dosageform, starch is present at an amount of about 70 mg, and mannitol ispresent at an amount that brings the total weight of composition toabout 125 mg. In some embodiments, the dosage form further comprisessodium stearyl fumarate at an amount of about 0.3 mg or about 0.32 mg.In some embodiments, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 1 mg potency of pomolidomide, about 70 mg pregelatinized starch;about 0.32 mg sodium stearyl fumarate; and spray dried mannitol at anamount that brings the total weight of the dosage form to 125 mg;wherein the dosage form is stable for a period of at least about 12,about 24, or about 36 months without refrigeration. In one embodiment,the dosage form is suitable for administration in a size 4 or largercapsule.

In another embodiment, provided herein is a dosage form comprisingpomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 2 mg potency of pomolidomide, which is stable for a period of atleast about 12, about 24, or about 36 months without refrigeration. Insome embodiments, the dosage form comprises mannitol and/or starch. Inone embodiment where both starch and mannitol are present in the dosageform, starch is present at an amount of about 140 mg, and mannitol ispresent at an amount that brings the total weight of composition toabout 250 mg. In some embodiments, the dosage form further comprisessodium stearyl fumarate at an amount of about 0.6 mg or about 0.64 mg.In some embodiments, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 2 mg potency of pomolidomide, about 140 mg pregelatinized starch;about 0.64 mg sodium stearyl fumarate; and spray dried mannitol at anamount that brings the total weight of the dosage form to 250 mg;wherein the dosage form is stable for a period of at least about 12,about 24, or about 36 months without refrigeration. In one embodiment,the dosage form is suitable for administration in a size 2 or largercapsule.

In another embodiment, provided herein is a dosage form comprisingpomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 5 mg potency of pomolidomide, which is stable for a period of atleast about 12, about 24, or about 36 months without refrigeration. Insome embodiments, the dosage form comprises mannitol and/or starch. Inone embodiment where both starch and mannitol are present in the dosageform, starch is present at an amount of about 168 mg, and mannitol ispresent at an amount that brings the total weight of composition toabout 300 mg. In some embodiments, the dosage form further comprisessodium stearyl fumarate at an amount of about 0.8 mg or about 0.75 mg.In some embodiments, provided herein is a dosage form comprising: 1)pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, present at an amount that providesabout 5 mg potency of pomolidomide, about 168 mg pregelatinized starch;about 0.75 mg sodium stearyl fumarate; and spray dried mannitol at anamount that brings the total weight of the dosage form to 300 mg;wherein the dosage form is stable for a period of at least 12, about 24,or about 36 months without refrigeration. In one embodiment, the dosageform is suitable for administration in a size 1 or larger capsule.

4.1.1 Second Active Agents

In certain embodiments, provided herein are compositions and dosage formof pomolidomide, or a pharmaceutically acceptable stereoisomer, prodrug,salt, solvate, or clathrate thereof, which may further comprise one ormore secondary active ingredients. Certain combinations may worksynergistically in the treatment of particular types diseases ordisorders, and conditions and symptoms associated with such diseases ordisorders. Pomolidomide, or a pharmaceutically acceptable stereoisomer,prodrug, salt, solvate, or clathrate thereof, can also work to alleviateadverse effects associated with certain second active agents, and viceversa.

Specific second active compounds that can be contained in theformulations and dosage forms provided herein vary depending on thespecific indication to be treated, prevented or managed.

For instance, for the treatment, prevention or management of cancer,second active agents include, but are not limited to: semaxanib;cyclosporin; etanercept; doxycycline; bortezomib; acivicin; aclarubicin;acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine;ambomycin; ametantrone acetate; amsacrine; anastrozole; anthramycin;asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat;benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate;bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan;cactinomycin; calusterone; caracemide; carbetimer; carboplatin;carmustine; carubicin hydrochloride; carzelesin; cedefingol; celecoxib;chlorambucil; cirolemycin; cisplatin; cladribine; crisnatol mesylate;cyclophosphamide; cytarabine; dacarbazine; dactinomycin; daunorubicinhydrochloride; decitabine; dexormaplatin; dezaguanine; dezaguaninemesylate; diaziquone; docetaxel; doxorubicin; doxorubicin hydrochloride;droloxifene; droloxifene citrate; dromostanolone propionate; duazomycin;edatrexate; eflornithine hydrochloride; elsamitrucin; enloplatin;enpromate; epipropidine; epirubicin hydrochloride; erbulozole;esorubicin hydrochloride; estramustine; estramustine phosphate sodium;etanidazole; etoposide; etoposide phosphate; etoprine; fadrozolehydrochloride; fazarabine; fenretinide; floxuridine; fludarabinephosphate; fluorouracil; flurocitabine; fosquidone; fostriecin sodium;gemcitabine; gemcitabine hydrochloride; hydroxyurea; idarubicinhydrochloride; ifosfamide; ilmofosine; iproplatin; irinotecan;irinotecan hydrochloride; lanreotide acetate; letrozole; leuprolideacetate; liarozole hydrochloride; lometrexol sodium; lomustine;losoxantrone hydrochloride; masoprocol; maytansine; mechlorethaminehydrochloride; megestrol acetate; melengestrol acetate; melphalan;menogaril; mercaptopurine; methotrexate; methotrexate sodium; metoprine;meturedepa; mitindomide; mitocarcin; mitocromin; mitogillin; mitomalcin;mitomycin; mitosper; mitotane; mitoxantrone hydrochloride; mycophenolicacid; nocodazole; nogalamycin; ormaplatin; oxisuran; paclitaxel;pegaspargase; peliomycin; pentamustine; peplomycin sulfate;perfosfamide; pipobroman; piposulfan; piroxantrone hydrochloride;plicamycin; plomestane; porfimer sodium; porfiromycin; prednimustine;procarbazine hydrochloride; puromycin; puromycin hydrochloride;pyrazofurin; riboprine; safingol; safingol hydrochloride; semustine;simtrazene; sparfosate sodium; sparsomycin; spirogermaniumhydrochloride; spiromustine; spiroplatin; streptonigrin; streptozocin;sulofenur; talisomycin; tecogalan sodium; taxotere; tegafur;teloxantrone hydrochloride; temoporfin; teniposide; teroxirone;testolactone; thiamiprine; thioguanine; thiotepa; tiazofurin;tirapazamine; toremifene citrate; trestolone acetate; triciribinephosphate; trimetrexate; trimetrexate glucuronate; triptorelin;tubulozole hydrochloride; uracil mustard; uredepa; vapreotide;verteporfin; vinblastine sulfate; vincristine sulfate; vindesine;vindesine sulfate; vinepidine sulfate; vinglycinate sulfate;vinleurosine sulfate; vinorelbine tartrate; vinrosidine sulfate;vinzolidine sulfate; vorozole; zeniplatin; zinostatin; and zorubicinhydrochloride.

Other second agents include, but are not limited to: 20-epi-1,25dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin;acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists;altretamine; ambamustine; amidox; amifostine; aminolevulinic acid;amrubicin; amsacrine; anagrelide; anastrozole; andrographolide;angiogenesis inhibitors; antagonist D; antagonist G; antarelix;anti-dorsalizing morphogenetic protein-1; antiandrogen, prostaticcarcinoma; antiestrogen; antineoplaston; antisense oligonucleotides;aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators;apurinic acid; ara-CDP-DL-PTBA; arginine deaminase; asulacrine;atamestane; atrimustine; axinastatin 1; axinastatin 2; axinastatin 3;azasetron; azatoxin; azatyrosine; baccatin III derivatives; balanol;batimastat; BCR/ABL antagonists; benzochlorins; benzoylstaurosporine;beta lactam derivatives; beta-alethine; betaclamycin B; betulinic acid;bFGF inhibitor; bicalutamide; bisantrene; bisaziridinylspermine;bisnafide; bistratene A; bizelesin; breflate; bropirimine; budotitane;buthionine sulfoximine; calcipotriol; calphostin C; camptothecinderivatives; capecitabine; carboxamide-amino-triazole;carboxyamidotriazole; CaRest M3; CARN 700; cartilage derived inhibitor;carzelesin; casein kinase inhibitors (ICOS); castanospermine; cecropinB; cetrorelix; chlorins; chloroquinoxaline sulfonamide; cicaprost;cis-porphyrin; cladribine; clomifene analogues; clotrimazole;collismycin A; collismycin B; combretastatin A4; combretastatinanalogue; conagenin; crambescidin 816; crisnatol; cryptophycin 8;cryptophycin A derivatives; curacin A; cyclopentanthraquinones;cycloplatam; cypemycin; cytarabine ocfosfate; cytolytic factor;cytostatin; dacliximab; decitabine; dehydrodidemnin B; deslorelin;dexamethasone; dexifosfamide; dexrazoxane; dexverapamil; diaziquone;didemnin B; didox; diethylnorspermine; dihydro-5-azacytidine;dihydrotaxol, 9-; dioxamycin; diphenyl spiromustine; docetaxel;docosanol; dolasetron; doxifluridine; doxorubicin; droloxifene;dronabinol; duocarmycin SA; ebselen; ecomustine; edelfosine;edrecolomab; eflornithine; elemene; emitefur; epirubicin; epristeride;estramustine analogue; estrogen agonists; estrogen antagonists;etanidazole; etoposide phosphate; exemestane; fadrozole; fazarabine;fenretinide; filgrastim; finasteride; flavopiridol; flezelastine;fluasterone; fludarabine; fluorodaunorunicin hydrochloride; forfenimex;formestane; fostriecin; fotemustine; gadolinium texaphyrin; galliumnitrate; galocitabine; ganirelix; gelatinase inhibitors; gemcitabine;glutathione inhibitors; hepsulfam; heregulin; hexamethylenebisacetamide; hypericin; ibandronic acid; idarubicin; idoxifene;idramantone; ilmofosine; ilomastat; imatinib (Gleevec®), imiquimod;immunostimulant peptides; insulin-like growth factor-1 receptorinhibitor; interferon agonists; interferons; interleukins; iobenguane;iododoxorubicin; ipomeanol, 4-; iroplact; irsogladine; isobengazole;isohomohalicondrin B; itasetron; jasplakinolide; kahalalide F;lamellarin-N triacetate; lanreotide; leinamycin; lenograstim; lentinansulfate; leptolstatin; letrozole; leukemia inhibiting factor; leukocytealpha interferon; leuprolide+estrogen+progesterone; leuprorelin;levamisole; liarozole; linear polyamine analogue; lipophilicdisaccharide peptide; lipophilic platinum compounds; lissoclinamide 7;lobaplatin; lombricine; lometrexol; lonidamine; losoxantrone;loxoribine; lurtotecan; lutetium texaphyrin; lysofylline; lyticpeptides; maitansine; mannostatin A; marimastat; masoprocol; maspin;matrilysin inhibitors; matrix metalloproteinase inhibitors; menogaril;merbarone; meterelin; methioninase; metoclopramide; MIF inhibitor;mifepristone; miltefosine; mirimostim; mitoguazone; mitolactol;mitomycin analogues; mitonafide; mitotoxin fibroblast growthfactor-saporin; mitoxantrone; mofarotene; molgramostim; Erbitux, humanchorionic gonadotrophin; monophosphoryl lipid A+myobacterium cell wallsk; mopidamol; mustard anticancer agent; mycaperoxide B; mycobacterialcell wall extract; myriaporone; N-acetyldinaline; N-substitutedbenzamides; nafarelin; nagrestip; naloxone+pentazocine; napavin;naphterpin; nartograstim; nedaplatin; nemorubicin; neridronic acid;nilutamide; nisamycin; nitric oxide modulators; nitroxide antioxidant;nitrullyn; oblimersen (Genasense®); O6-benzylguanine; octreotide;okicenone; oligonucleotides; onapristone; ondansetron; ondansetron;oracin; oral cytokine inducer; ormaplatin; osaterone; oxaliplatin;oxaunomycin; paclitaxel; paclitaxel analogues; paclitaxel derivatives;palauamine; palmitoylrhizoxin; pamidronic acid; panaxytriol; panomifene;parabactin; pazelliptine; pegaspargase; peldesine; pentosan polysulfatesodium; pentostatin; pentrozole; perflubron; perfosfamide; perillylalcohol; phenazinomycin; phenylacetate; phosphatase inhibitors;picibanil; pilocarpine hydrochloride; pirarubicin; piritrexim; placetinA; placetin B; plasminogen activator inhibitor; platinum complex;platinum compounds; platinum-triamine complex; porfimer sodium;porfiromycin; prednisone; propyl bis-acridone; prostaglandin J2;proteasome inhibitors; protein A-based immune modulator; protein kinaseC inhibitor; protein kinase C inhibitors, microalgal; protein tyrosinephosphatase inhibitors; purine nucleoside phosphorylase inhibitors;purpurins; pyrazoloacridine; pyridoxylated hemoglobin polyoxyethyleneconjugate; raf antagonists; raltitrexed; ramosetron; ras farnesylprotein transferase inhibitors; ras inhibitors; ras-GAP inhibitor;retelliptine demethylated; rhenium Re 186 etidronate; rhizoxin;ribozymes; RII retinamide; rohitukine; romurtide; roquinimex; rubiginoneB1; ruboxyl; safingol; saintopin; SarCNU; sarcophytol A; sargramostim;Sdi 1 mimetics; semustine; senescence derived inhibitor 1; senseoligonucleotides; signal transduction inhibitors; sizofiran; sobuzoxane;sodium borocaptate; sodium phenylacetate; solverol; somatomedin bindingprotein; sonermin; sparfosic acid; spicamycin D; spiromustine;splenopentin; spongistatin 1; squalamine; stipiamide; stromelysininhibitors; sulfinosine; superactive vasoactive intestinal peptideantagonist; suradista; suramin; swainsonine; tallimustine; tamoxifenmethiodide; tauromustine; tazarotene; tecogalan sodium; tegafur;tellurapyrylium; telomerase inhibitors; temoporfin; teniposide;tetrachlorodecaoxide; tetrazomine; thaliblastine; thiocoraline;thrombopoietin; thrombopoietin mimetic; thymalfasin; thymopoietinreceptor agonist; thymotrinan; thyroid stimulating hormone; tin ethyletiopurpurin; tirapazamine; titanocene bichloride; topsentin;toremifene; translation inhibitors; tretinoin; triacetyluridine;triciribine; trimetrexate; triptorelin; tropisetron; turosteride;tyrosine kinase inhibitors; tyrphostins; UBC inhibitors; ubenimex;urogenital sinus-derived growth inhibitory factor; urokinase receptorantagonists; vapreotide; variolin B; velaresol; veramine; verdins;verteporfin; vinorelbine; vinxaltine; vitaxin; vorozole; zanoterone;zeniplatin; zilascorb; and zinostatin stimalamer.

Yet other second active agents include, but are not limited to,2-methoxyestradiol, telomestatin, inducers of apoptosis in multiplemyeloma cells (such as, for example, TRAIL), statins, semaxanib,cyclosporin, etanercept, doxycycline, bortezomib, oblimersen(Genasense®), remicade, docetaxel, celecoxib, melphalan, dexamethasone(Decadron®), steroids, gemcitabine, cisplatinum, temozolomide,etoposide, cyclophosphamide, temodar, carboplatin, procarbazine,gliadel, tamoxifen, topotecan, methotrexate, Arisa®, taxol, taxotere,fluorouracil, leucovorin, irinotecan, xeloda, CPT-11, interferon alpha,pegylated interferon alpha (e.g., PEG INTRON-A), capecitabine,cisplatin, thiotepa, fludarabine, carboplatin, liposomal daunorubicin,cytarabine, doxetaxol, pacilitaxel, vinblastine, IL-2, GM-CSF,dacarbazine, vinorelbine, zoledronic acid, palmitronate, biaxin,busulphan, prednisone, bisphosphonate, arsenic trioxide, vincristine,doxorubicin (Doxil®), paclitaxel, ganciclovir, adriamycin, estramustinesodium phosphate (Emcyt®), sulindac, and etoposide.

In another embodiment, examples of specific second agents according tothe indications to be treated, prevented, or managed can be found in thefollowing references, all of which are incorporated herein in theirentireties: U.S. Pat. Nos. 6,281,230 and 5,635,517; U.S. publicationnos. 2004/0220144, 2004/0190609, 2004/0087546, 2005/0203142,2004/0091455, 2005/0100529, 2005/0214328, 2005/0239842, 2006/0154880,2006/0122228, and 2005/0143344; and U.S. provisional application No.60/631,870.

Examples of second active agents that may be used for the treatment,prevention and/or management of pain include, but are not limited to,conventional therapeutics used to treat or prevent pain such asantidepressants, anticonvulsants, antihypertensives, anxiolytics,calcium channel blockers, muscle relaxants, non-narcotic analgesics,opioid analgesics, anti-inflammatories, cox-2 inhibitors,immunomodulatory agents, alpha-adrenergic receptor agonists orantagonists, immunosuppressive agents, corticosteroids, hyperbaricoxygen, ketamine, other anesthetic agents, NMDA antagonists, and othertherapeutics found, for example, in the Physician's Desk Reference 2003.Specific examples include, but are not limited to, salicylic acidacetate (Aspirin®), celecoxib (Celebrex®), Enbrel®, ketamine, gabapentin(Neurontin®), phenytoin (Dilantin®), carbamazepine (Tegretol®),oxcarbazepine (Trileptal®), valproic acid (Depakene®), morphine sulfate,hydromorphone, prednisone, griseofulvin, penthonium, alendronate,dyphenhydramide, guanethidine, ketorolac (Acular®), thyrocalcitonin,dimethylsulfoxide (DMSO), clonidine (Catapress®), bretylium, ketanserin,reserpine, droperidol, atropine, phentolamine, bupivacaine, lidocaine,acetaminophen, nortriptyline (Pamelor®), amitriptyline (Elavil®),imipramine (Tofranil®), doxepin (Sinequan®), clomipramine (Anafranil®),fluoxetine (Prozac®), sertraline (Zoloft®), naproxen, nefazodone(Serzone®), venlafaxine (Effexor®), trazodone (Desyrel®), bupropion(Wellbutrin®), mexiletine, nifedipine, propranolol, tramadol,lamotrigine, vioxx, ziconotide, ketamine, dextromethorphan,benzodiazepines, baclofen, tizanidine and phenoxybenzamine.

Examples of second active agents that may be used for the treatment,prevention and/or management of macular degeneration and relatedsyndromes include, but are not limited to, a steroid, a lightsensitizer, an integrin, an antioxidant, an interferon, a xanthinederivative, a growth hormone, a neutrotrophic factor, a regulator ofneovascularization, an anti-VEGF antibody, a prostaglandin, anantibiotic, a phytoestrogen, an anti-inflammatory compound or anantiangiogenesis compound, or a combination thereof. Specific examplesinclude, but are not limited to, verteporfin, purlytin, an angiostaticsteroid, rhuFab, interferon-2α, pentoxifylline, tin etiopurpurin,motexafin, lucentis, lutetium, 9-fluoro-11,21-dihydroxy-16,17-1-methylethylidinebis(oxy)pregna-1,4-diene-3,20-dione, latanoprost(see U.S. Pat. No. 6,225,348), tetracycline and its derivatives,rifamycin and its derivatives, macrolides, metronidazole (U.S. Pat. Nos.6,218,369 and 6,015,803), genistein, genistin, 6′-O-Mal genistin,6′-O—Ac genistin, daidzein, daidzin, 6′-O-Mal daidzin, 6′-O—Ac daidzin,glycitein, glycitin, 6′-O-Mal glycitin, biochanin A, formononetin (U.S.Pat. No. 6,001,368), triamcinolone acetomide, dexamethasone (U.S. Pat.No. 5,770,589), thalidomide, glutathione (U.S. Pat. No. 5,632,984),basic fibroblast growth factor (bFGF), transforming growth factor b(TGF-b), brain-derived neurotrophic factor (BDNF), plasminogen activatorfactor type 2 (PAI-2), EYE101 (Eyetech Pharmaceuticals), LY333531 (EliLilly), Miravant, and RETISERT implant (Bausch & Lomb). All of thereferences cited herein are incorporated in their entireties byreference.

Examples of second active agents that may be used for the treatment,prevention and/or management of skin diseases include, but are notlimited to, keratolytics, retinoids, α-hydroxy acids, antibiotics,collagen, botulinum toxin, interferon, steroids, and immunomodulatoryagents. Specific examples include, but are not limited to,5-fluorouracil, masoprocol, trichloroacetic acid, salicylic acid, lacticacid, ammonium lactate, urea, tretinoin, isotretinoin, antibiotics,collagen, botulinum toxin, interferon, corticosteroid, transretinoicacid and collagens such as human placental collagen, animal placentalcollagen, Dermalogen, AlloDerm, Fascia, Cymetra, Autologen, Zyderm,Zyplast, Resoplast, and Isolagen.

Examples of second active agents that may be used for the treatment,prevention and/or management of pulmonary hepertension and relateddisorders include, but are not limited to, anticoagulants, diuretics,cardiac glycosides, calcium channel blockers, vasodilators, prostacyclinanalogues, endothelin antagonists, phosphodiesterase inhibitors (e.g.,PDE V inhibitors), endopeptidase inhibitors, lipid lowering agents,thromboxane inhibitors, and other therapeutics known to reduce pulmonaryartery pressure. Specific examples include, but are not limited to,warfarin (Coumadin®), a diuretic, a cardiac glycoside, digoxin-oxygen,diltiazem, nifedipine, a vasodilator such as prostacyclin (e.g.,prostaglandin 12 (PGI2), epoprostenol (EPO, Floran®), treprostinil(Remodulin®), nitric oxide (NO), bosentan (Tracleer®), amlodipine,epoprostenol (Florae), treprostinil (Remodulin®), prostacyclin,tadalafil (Cialis®), simvastatin (Zocor®), omapatrilat (Vanlev®),irbesartan (Avapro®), pravastatin (Pravachol®), digoxin, L-arginine,iloprost, betaprost, and sildenafil (Viagra®).

Examples of second active agents that may be used for the treatment,prevention and/or management of asbestos-related disorders include, butare not limited to, anthracycline, platinum, alkylating agent,oblimersen (Genasense®), cisplatinum, cyclophosphamide, temodar,carboplatin, procarbazine, gliadel, tamoxifen, topotecan, methotrexate,taxotere, irinotecan, capecitabine, cisplatin, thiotepa, fludarabine,carboplatin, liposomal daunorubicin, cytarabine, doxetaxol, pacilitaxel,vinblastine, IL-2, GM-CSF, dacarbazine, vinorelbine, zoledronic acid,palmitronate, biaxin, busulphan, prednisone, bisphosphonate, arsenic,trioxide, vincristine, doxorubicin (Doxil®), paclitaxel, ganciclovir,adriamycin, bleomycin, hyaluronidase, mitomycin C, mepacrine, thiotepa,tetracycline and gemcitabine.

Examples of second active agents that may be used for the treatment,prevention and/or management of parasitic diseases include, but are notlimited to, chloroquine, quinine, quinidine, pyrimethamine,sulfadiazine, doxycycline, clindamycin, mefloquine, halofantrine,primaquine, hydroxychloroquine, proguanil, atovaquone, azithromycin,suramin, pentamidine, melarsoprol, nifurtimox, benznidazole,amphotericin B, pentavalent antimony compounds (e.g., sodiumstiboglucuronate), interfereon gamma, itraconazole, a combination ofdead promastigotes and BCG, leucovorin, corticosteroids, sulfonamide,spiramycin, IgG (serology), trimethoprim, and sulfamethoxazole.

Examples of second active agents that may be used for the treatment,prevention and/or management of immunodeficiency disorders include, butare not limited to: antibiotics (therapeutic or prophylactic) such as,but not limited to, ampicillin, tetracycline, penicillin,cephalosporins, streptomycin, kanamycin, and erythromycin; antiviralssuch as, but not limited to, amantadine, rimantadine, acyclovir, andribavirin; immunoglobulin; plasma; immunologic enhancing drugs such as,but not limited to, levami sole and isoprinosine; biologics such as, butnot limited to, gammaglobulin, transfer factor, interleukins, andinterferons; hormones such as, but not limited to, thymic; and otherimmunologic agents such as, but not limited to, B cell stimulators(e.g., BAFF/BlyS), cytokines (e.g., IL-2, IL-4, and IL-5), growthfactors (e.g., TGF-α), antibodies (e.g., anti-CD40 and IgM),oligonucleotides containing unmethylated CpG motifs, and vaccines (e.g.,viral and tumor peptide vaccines).

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS disorders include, but are notlimited to: opioids; a dopamine agonist or antagonist, such as, but notlimited to, Levodopa, L-DOPA, cocaine, α-methyl-tyrosine, reserpine,tetrabenazine, benzotropine, pargyline, fenodolpam mesylate,cabergoline, pramipexole dihydrochloride, ropinorole, amantadinehydrochloride, selegiline hydrochloride, carbidopa, pergolide mesylate,Sinemet CR, and Symmetrel; a MAO inhibitor, such as, but not limited to,iproniazid, clorgyline, phenelzine and isocarboxazid; a COMT inhibitor,such as, but not limited to, tolcapone and entacapone; a cholinesteraseinhibitor, such as, but not limited to, physostigmine saliclate,physostigmine sulfate, physostigmine bromide, meostigmine bromide,neostigmine methylsulfate, ambenonim chloride, edrophonium chloride,tacrine, pralidoxime chloride, obidoxime chloride, trimedoxime bromide,diacetyl monoxim, endrophonium, pyridostigmine, and demecarium; ananti-inflammatory agent, such as, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, Rho-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone or betamethasone and other glucocorticoids; and anantiemetic agent, such as, but not limited to, metoclopromide,domperidone, prochlorperazine, promethazine, chlorpromazine,trimethobenzamide, ondansetron, granisetron, hydroxyzine, acetylleucinemonoethanolamine, alizapride, azasetron, benzquinamide, bietanautine,bromopride, buclizine, clebopride, cyclizine, dimenhydrinate,diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone,oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of CNS injuries and related syndromesinclude, but are not limited to, immunomodulatory agents,immunosuppressive agents, antihypertensives, anticonvulsants,fibrinolytic agents, antiplatelet agents, antipsychotics,antidepressants, benzodiazepines, buspirone, amantadine, and other knownor conventional agents used in patients with CNS injury/damage andrelated syndromes. Specific examples include, but are not limited to:steroids (e.g., glucocorticoids, such as, but not limited to,methylprednisolone, dexamethasone and betamethasone); ananti-inflammatory agent, including, but not limited to, naproxen sodium,diclofenac sodium, diclofenac potassium, celecoxib, sulindac, oxaprozin,diflunisal, etodolac, meloxicam, ibuprofen, ketoprofen, nabumetone,refecoxib, methotrexate, leflunomide, sulfasalazine, gold salts, RHo-DImmune Globulin, mycophenylate mofetil, cyclosporine, azathioprine,tacrolimus, basiliximab, daclizumab, salicylic acid, acetylsalicylicacid, methyl salicylate, diflunisal, salsalate, olsalazine,sulfasalazine, acetaminophen, indomethacin, sulindac, mefenamic acid,meclofenamate sodium, tolmetin, ketorolac, dichlofenac, flurbinprofen,oxaprozin, piroxicam, meloxicam, ampiroxicam, droxicam, pivoxicam,tenoxicam, phenylbutazone, oxyphenbutazone, antipyrine, aminopyrine,apazone, zileuton, aurothioglucose, gold sodium thiomalate, auranofin,methotrexate, colchicine, allopurinol, probenecid, sulfinpyrazone andbenzbromarone; a cAMP analog including, but not limited to, db-cAMP; anagent comprising a methylphenidate drug, which comprises1-threo-methylphenidate, d-threo-methylphenidate,dl-threo-methylphenidate, 1-erythro-methylphenidate,d-erythro-methylphenidate, dl-erythro-methylphenidate, and a mixturethereof; and a diuretic agent such as, but not limited to, mannitol,furosemide, glycerol, and urea.

Examples of second active agent that may be used for the treatment,prevention and/or management of dysfunctional sleep and relatedsyndromes include, but are not limited to, a tricyclic antidepressantagent, a selective serotonin reuptake inhibitor, an antiepileptic agent(gabapentin, pregabalin, carbamazepine, oxcarbazepine, levitiracetam,topiramate), an antiaryhthmic agent, a sodium channel blocking agent, aselective inflammatory mediator inhibitor, an opioid agent, a secondimmunomodulatory compound, a combination agent, and other known orconventional agents used in sleep therapy. Specific examples include,but are not limited to, Neurontin, oxycontin, morphine, topiramate,amitryptiline, nortryptiline, carbamazepine, Levodopa, L-DOPA, cocaine,α-methyl-tyrosine, reserpine, tetrabenazine, benzotropine, pargyline,fenodolpam mesylate, cabergoline, pramipexole dihydrochloride,ropinorole, amantadine hydrochloride, selegiline hydrochloride,carbidopa, pergolide mesylate, Sinemet CR, Symmetrel, iproniazid,clorgyline, phenelzine, isocarboxazid, tolcapone, entacapone,physostigmine saliclate, physostigmine sulfate, physostigmine bromide,meostigmine bromide, neostigmine methylsulfate, ambenonim chloride,edrophonium chloride, tacrine, pralidoxime chloride, obidoxime chloride,trimedoxime bromide, diacetyl monoxim, endrophonium, pyridostigmine,demecarium, naproxen sodium, diclofenac sodium, diclofenac potassium,celecoxib, sulindac, oxaprozin, diflunisal, etodolac, meloxicam,ibuprofen, ketoprofen, nabumetone, refecoxib, methotrexate, leflunomide,sulfasalazine, gold salts, RHo-D Immune Globulin, mycophenylate mofetil,cyclosporine, azathioprine, tacrolimus, basiliximab, daclizumab,salicylic acid, acetylsalicylic acid, methyl salicylate, diflunisal,salsalate, olsalazine, sulfasalazine, acetaminophen, indomethacin,sulindac, mefenamic acid, meclofenamate sodium, tolmetin, ketorolac,dichlofenac, flurbinprofen, oxaprozin, piroxicam, meloxicam,ampiroxicam, droxicam, pivoxicam, tenoxicam, phenylbutazone,oxyphenbutazone, antipyrine, aminopyrine, apazone, zileuton,aurothioglucose, gold sodium thiomalate, auranofin, methotrexate,colchicine, allopurinol, probenecid, sulfinpyrazone, benzbromarone,betamethasone and other glucocorticoids, metoclopromide, domperidone,prochlorperazine, promethazine, chlorpromazine, trimethobenzamide,ondansetron, granisetron, hydroxyzine, acetylleucine monoethanolamine,alizapride, azasetron, benzquinamide, bietanautine, bromopride,buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol,dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl,pipamazine, scopolamine, sulpiride, tetrahydrocannabinol,thiethylperazine, thioproperazine, tropisetron, and a mixture thereof.

Examples of second active agents that may be used for the treatment,prevention and/or management of hemoglobinopathy and related disordersinclude, but are not limited to: interleukins, such as IL-2 (includingrecombinant IL-II (“rIL2”) and canarypox IL-2), IL-10, IL-12, and IL-18;interferons, such as interferon alfa-2a, interferon alfa-2b, interferonalfa-n1, interferon alfa-n3, interferon beta-I a, and interferon gamma-Ib; and G-CSF; hydroxyurea; butyrates or butyrate derivatives; nitrousoxide; hydroxy urea; HEMOXIN™ (NIPRISAN™; see U.S. Pat. No. 5,800,819);Gardos channel antagonists such as clotrimazole and triaryl methanederivatives; Deferoxamine; protein C; and transfusions of blood, or of ablood substitute such as Hemospan™ or Hemospan™ PS (Sangart).

4.2. Process for Making Dosage Forms

Dosage forms provided herein can be prepared by any of the methods ofpharmacy, but all methods include the step of bringing the activeingredient into association with the excipient, which constitutes one ormore necessary ingredients. In general, the compositions are prepared byuniformly admixing (e.g., direct blend) the active ingredient withliquid excipients or finely divided solid excipients or both, and then,if necessary, shaping the product into the desired presentation (e.g.,compaction such as roller-compaction). If desired, tablets can be coatedby standard aqueous or non-aqueous techniques.

A dosage form provided herein can be prepared by compression or molding,optionally with one or more accessory ingredients. Compressed tabletscan be prepared by compressing in a suitable machine the activeingredient in a free-flowing form such as powder or granules, optionallymixed with an excipient as above and/or a surface active or dispersingagent. Molded tablets can be made by molding in a suitable machine amixture of the powdered compound moistened with an inert liquid diluent.Encapsulation of the dosage forms provided herein can be done usingcapsules of methylcellulose, calcium alginate, or gelatin.

In some embodiments, the active ingredients and excipients are directlyblended and loaded into, for example, a capsule, or compressed directlyinto tablets. A direct-blended dosage form may be more advantageous thana compacted (e.g., roller-compacted) dosage form in certain instances,since direct-blending can reduce or eliminate the harmful health effectsthat may be caused by airborne particles of ingredients during themanufacture using compaction process.

Direct blend formulations may be advantageous in certain instancesbecause they require only one blending step, that of the active andexcipients, before being processed into the final dosage form, e.g.,tablet or capsule. This can reduce the production of airborne particleor dust to a minimum, while roller-compaction processes may be prone toproduce dust. In roller-compaction process, the compacted material isoften milled into smaller particles for further processing. The millingoperation can produce significant amounts of airborne particles, sincethe purpose for this step in manufacturing is to reduce the materialsparticle size. The milled material is then blended with otheringredients prior to manufacturing the final dosage form.

For certain active ingredients, in particular for a compound with a lowsolubility, the active ingredient's particle size is reduced to a finepowder in order to help increase the active ingredient's rate ofsolubilization. The increase in the rate of solubilization is oftennecessary for the active ingredient to be effectively absorbed in thegastrointestinal tract. However for fine powders to be directly-blendedand loaded onto capsules, the excipients should preferably providecertain characteristics which render the ingredients suitable for thedirect-blend process. Examples of such characteristics include, but arenot limited to, acceptable flow characteristics. In one embodiment,therefore, provided herein is the use of, and compositions comprising,excipients which may provide characteristics, which render the resultingmixture suitable for direct-blend process, e.g., good flowcharacteristics.

4.2.1. Screening

The process for making the pharmaceutical compositions of the inventionpreferably includes the screening of the active ingredient and theexcipient(s). In one embodiment, the active ingredient is passed througha screen having openings of about 200 microns to about 750 microns. Inanother embodiment, the active ingredient is passed through a screenwith openings of about 200 microns to about 400 microns. In oneembodiment, the active ingredient is passed through a screen havingopenings of about 300 to about 400 microns. Depending on theexcipient(s) used, the screen openings vary. For example, disintegrantsand binders are passed through openings of about 430 microns to about750 microns, from about 600 microns to about 720 microns, or about 710microns. Lubricants are typically passed through smaller openings, e.g.,about 150 microns to about 250 microns screen. In one embodiment, thelubricant is passed through a screen opening of about 210 microns.

4.2.2. Pre-Blending

After the ingredients are screened, the excipient and active ingredientare mixed in a diffusion mixer. In one embodiment, the mixing time isfrom about 1 minute to about 50 minutes, from about 5 minutes to about45 minutes, from about 10 minutes to about 40 minutes, or from about 10minutes to about 25 minutes. In another embodiment, the mixing time isabout 15 minutes.

When more than one excipients are used, the excipients may be admixed ina tumble blender for about 1 minute to about 20 minutes, or for about 5minutes to about 10 minutes, prior to mixing with the active ingredient.

4.2.3. Roller Compaction

In one embodiment, the pre-blend may optionally be passed through aroller compactor with a hammer mill attached at the discharge of thecompactor.

4.2.4. Final Blend

When a lubricant, e.g., sodium stearyl fumarate, is used, the lubricantis mixed with the pre-blend at the end of the process to complete thepharmaceutical composition. This additional mixing is from about 1minute to about 10 minutes, or from about 3 minutes to about 5 minutes.

4.2.5. Encapsulation

The formulation mixture is then encapsulated into the desired sizecapsule shell using, for example, a capsule filling machine or a rotarytablet press.

4.3. Kits

Pharmaceutical packs or kits which comprise pharmaceutical compositionsor dosage forms provided herein are also provided. An example of a kitcomprises notice in the form prescribed by a governmental agencyregulating the manufacture, use or sale of pharmaceuticals or biologicalproducts, which notice reflects approval by the agency of manufacture,use or sale for human administration.

4.4. Methods of Treatment, Prevention, and Management

Provided herein are methods of treating, preventing, and/or managingcertain diseases or disorders using the formulations, compositions, ordosage forms provided herein.

Examples of diseases or disorders include, but are not limited to,cancer, disorders associated with angiogenesis, pain including, but notlimited to, Complex Regional Pain Syndrome (“CRPS”), MacularDegeneration (“MD”) and related syndromes, skin diseases, pulmonarydisorders, asbestos-related disorders, parasitic diseases,immunodeficiency disorders, CNS disorders, CNS injury, atherosclerosisand related disorders, dysfunctional sleep and related disorders,hemoglobinopathy and related disorders (e.g., anemia), TNFα relateddisorders, and other various diseases and disorders.

Examples of cancer and precancerous conditions include, but are notlimited to, those described in U.S. Pat. Nos. 6,281,230 and 5,635,517 toMuller et al., in various U.S. patent publications to Zeldis, includingpublication nos. 2004/0220144A1, published Nov. 4, 2004 (Treatment ofMyelodysplastic Syndrome); 2004/0029832A1, published Feb. 12, 2004(Treatment of Various Types of Cancer); and 2004/0087546, published May6, 2004 (Treatment of Myeloproliferative Diseases). Examples alsoinclude those described in WO 2004/103274, published Dec. 2, 2004. Allof these references are incorporated herein in their entireties byreference.

Certain examples of cancer include, but are not limited to, cancers ofthe skin, such as melanoma; lymph node; breast; cervix; uterus;gastrointestinal tract; lung; ovary; prostate; colon; rectum; mouth;brain; head and neck; throat; testes; kidney; pancreas; bone; spleen;liver; bladder; larynx; nasal passages; and AIDS-related cancers. Thecompounds are also useful for treating cancers of the blood and bonemarrow, such as multiple myeloma and acute and chronic leukemias, forexample, lymphoblastic, myelogenous, lymphocytic, and myelocyticleukemias. The compounds provided herein can be used for treating,preventing or managing either primary or metastatic tumors.

Other cancers include, but are not limited to, advanced malignancy,amyloidosis, neuroblastoma, meningioma, hemangiopericytoma, multiplebrain metastase, glioblastoma multiforms, glioblastoma, brain stemglioma, poor prognosis malignant brain tumor, malignant glioma,recurrent malignant glioma, anaplastic astrocytoma, anaplasticoligodendroglioma, neuroendocrine tumor, rectal adenocarcinoma, Dukes C& D colorectal cancer, unresectable colorectal carcinoma, metastatichepatocellular carcinoma, Kaposi's sarcoma, karotype acute myeloblasticleukemia, chronic lymphocytic leukemia (CLL), Hodgkin's lymphoma,non-Hodgkin's lymphoma, cutaneous T-Cell lymphoma, cutaneous B-Celllymphoma, diffuse large B-Cell lymphoma, low grade follicular lymphoma,metastatic melanoma (localized melanoma, including, but not limited to,ocular melanoma), malignant mesothelioma, malignant pleural effusionmesothelioma syndrome, peritoneal carcinoma, papillary serous carcinoma,gynecologic sarcoma, soft tissue sarcoma, scleroderma, cutaneousvasculitis, Langerhans cell histiocytosis, leiomyosarcoma,fibrodysplasia ossificans progressive, hormone refractory prostatecancer, resected high-risk soft tissue sarcoma, unrescectablehepatocellular carcinoma, Waldenstrom's macroglobulinemia, smolderingmyeloma, indolent myeloma, fallopian tube cancer, androgen independentprostate cancer, androgen dependent stage IV non-metastatic prostatecancer, hormone-insensitive prostate cancer, chemotherapy-insensitiveprostate cancer, papillary thyroid carcinoma, follicular thyroidcarcinoma, medullary thyroid carcinoma, and leiomyoma. In a specificembodiment, the cancer is metastatic. In another embodiment, the canceris refractory or resistance to chemotherapy or radiation.

In one embodiment, the diseases or disorders are various forms ofleukemias such as chronic lymphocytic leukemia, chronic myelocyticleukemia, acute lymphoblastic leukemia, acute myelogenous leukemia andacute myeloblastic leukemia, including leukemias that are relapsed,refractory or resistant, as disclosed in U.S. publication no.2006/0030594, published Feb. 9, 2006, which is incorporated in itsentirety by reference.

The term “leukemia” refers malignant neoplasms of the blood-formingtissues. The leukemia includes, but is not limited to, chroniclymphocytic leukemia, chronic myelocytic leukemia, acute lymphoblasticleukemia, acute myelogenous leukemia and acute myeloblastic leukemia.The leukemia can be relapsed, refractory or resistant to conventionaltherapy. The term “relapsed” refers to a situation where patients whohave had a remission of leukemia after therapy have a return of leukemiacells in the marrow and a decrease in normal blood cells. The term“refractory or resistant” refers to a circumstance where patients, evenafter intensive treatment, have residual leukemia cells in their marrow.

In another embodiment, the diseases or disorders are various types oflymphomas, including Non-Hodgkin's lymphoma (NHL). The term “lymphoma”refers a heterogenous group of neoplasms arising in thereticuloendothelial and lymphatic systems. “NHL” refers to malignantmonoclonal proliferation of lymphoid cells in sites of the immunesystem, including lymph nodes, bone marrow, spleen, liver andgastrointestinal tract. Examples of NHL include, but are not limited to,mantle cell lymphoma (MCL), lymphocytic lymphoma of intermediatedifferentiation, intermediate lymphocytic lymphoma (ILL), diffuse poorlydifferentiated lymphocytic lymphoma (PDL), centrocytic lymphoma, diffusesmall-cleaved cell lymphoma (DSCCL), follicular lymphoma, and any typeof the mantle cell lymphomas that can be seen under the microscope(nodular, diffuse, blastic and mentle zone lymphoma).

Examples of diseases and disorders associated with, or characterized by,undesired angiogenesis include, but are not limited to, inflammatorydiseases, autoimmune diseases, viral diseases, genetic diseases,allergic diseases, bacterial diseases, ocular neovascular diseases,choroidal neovascular diseases, retina neovascular diseases, andrubeosis (neovascularization of the angle). Specific examples of thediseases and disorders associated with, or characterized by, undesiredangiogenesis include, but are not limited to, arthritis, endometriosis,Crohn's disease, heart failure, advanced heart failure, renalimpairment, endotoxemia, toxic shock syndrome, osteoarthritis,retrovirus replication, wasting, meningitis, silica-induced fibrosis,asbestos-induced fibrosis, veterinary disorder, malignancy-associatedhypercalcemia, stroke, circulatory shock, periodontitis, gingivitis,macrocytic anemia, refractory anemia, and 5q-deletion syndrome.

Examples of pain include, but are not limited to those described in U.S.patent publication no. 2005/0203142, published Sep. 15, 2005, which isincorporated herein by reference. Specific types of pain include, butare not limited to, nociceptive pain, neuropathic pain, mixed pain ofnociceptive and neuropathic pain, visceral pain, migraine, headache andpost-operative pain.

Examples of nociceptive pain include, but are not limited to, painassociated with chemical or thermal burns, cuts of the skin, contusionsof the skin, osteoarthritis, rheumatoid arthritis, tendonitis, andmyofascial pain.

Examples of neuropathic pain include, but are not limited to, CRPS typeI, CRPS type II, reflex sympathetic dystrophy (RSD), reflexneurovascular dystrophy, reflex dystrophy, sympathetically maintainedpain syndrome, causalgia, Sudeck atrophy of bone, algoneurodystrophy,shoulder hand syndrome, post-traumatic dystrophy, trigeminal neuralgia,post herpetic neuralgia, cancer related pain, phantom limb pain,fibromyalgia, chronic fatigue syndrome, spinal cord injury pain, centralpost-stroke pain, radiculopathy, diabetic neuropathy, post-stroke pain,luetic neuropathy, and other painful neuropathic conditions such asthose induced by drugs such as vincristine and velcade.

As used herein, the terms “complex regional pain syndrome,” “CRPS” and“CRPS and related syndromes” mean a chronic pain disorder characterizedby one or more of the following: pain, whether spontaneous or evoked,including allodynia (painful response to a stimulus that is not usuallypainful) and hyperalgesia (exaggerated response to a stimulus that isusually only mildly painful); pain that is disproportionate to theinciting event (e.g., years of severe pain after an ankle sprain);regional pain that is not limited to a single peripheral nervedistribution; and autonomic dysregulation (e.g., edema, alteration inblood flow and hyperhidrosis) associated with trophic skin changes (hairand nail growth abnormalities and cutaneous ulceration).

Examples of MD and related syndromes include, but are not limited to,those described in U.S. patent publication no. 2004/0091455, publishedMay 13, 2004, which is incorporated herein by reference. Specificexamples include, but are not limited to, atrophic (dry) MD, exudative(wet) MD, age-related maculopathy (ARM), choroidal neovascularisation(CNVM), retinal pigment epithelium detachment (PED), and atrophy ofretinal pigment epithelium (RPE).

Examples of skin diseases include, but are not limited to, thosedescribed in U.S. publication no. 2005/0214328A1, published Sep. 29,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, keratoses and related symptoms, skindiseases or disorders characterized with overgrowths of the epidermis,acne, and wrinkles.

As used herein, the term “keratosis” refers to any lesion on theepidermis marked by the presence of circumscribed overgrowths of thehorny layer, including but not limited to actinic keratosis, seborrheickeratosis, keratoacanthoma, keratosis follicularis (Darier disease),inverted follicular keratosis, palmoplantar keratoderma (PPK, keratosispalmaris et plantaris), keratosis pilaris, and stucco keratosis. Theterm “actinic keratosis” also refers to senile keratosis, keratosissenilis, verruca senilis, plana senilis, solar keratosis, keratoderma orkeratoma. The term “seborrheic keratosis” also refers to seborrheicwart, senile wart, or basal cell papilloma. Keratosis is characterizedby one or more of the following symptoms: rough appearing, scaly,erythematous papules, plaques, spicules or nodules on exposed surfaces(e.g., face, hands, ears, neck, legs and thorax), excrescences ofkeratin referred to as cutaneous horns, hyperkeratosis, telangiectasias,elastosis, pigmented lentigines, acanthosis, parakeratosis,dyskeratoses, papillomatosis, hyperpigmentation of the basal cells,cellular atypia, mitotic figures, abnormal cell-cell adhesion, denseinflammatory infiltrates and small prevalence of squamous cellcarcinomas.

Examples of skin diseases or disorders characterized with overgrowths ofthe epidermis include, but are not limited to, any conditions, diseasesor disorders marked by the presence of overgrowths of the epidermis,including but not limited to, infections associated with papillomavirus, arsenical keratoses, sign of Leser-Trélat, warty dyskeratoma(WD), trichostasis spinulosa (TS), erythrokeratodermia variabilis (EKV),ichthyosis fetalis (harlequin ichthyosis), knuckle pads, cutaneousmelanoacanthoma, porokeratosis, psoriasis, squamous cell carcinoma,confluent and reticulated papillomatosis (CRP), acrochordons, cutaneoushorn, cowden disease (multiple hamartoma syndrome), dermatosis papulosanigra (DPN), epidermal nevus syndrome (ENS), ichthyosis vulgaris,molluscum contagiosum, prurigo nodularis, and acanthosis nigricans (AN).

Examples of pulmonary disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0239842A1, published Oct. 27,2005, which is incorporated herein by reference. Specific examplesinclude pulmonary hypertension and related disorders. Examples ofpulmonary hypertension and related disorders include, but are notlimited to: primary pulmonary hypertension (PPH); secondary pulmonaryhypertension (SPH); familial PPH; sporadic PPH; precapillary pulmonaryhypertension; pulmonary arterial hypertension (PAH); pulmonary arteryhypertension; idiopathic pulmonary hypertension; thrombotic pulmonaryarteriopathy (TPA); plexogenic pulmonary arteriopathy; functionalclasses I to IV pulmonary hypertension; and pulmonary hypertensionassociated with, related to, or secondary to, left ventriculardysfunction, mitral valvular disease, constrictive pericarditis, aorticstenosis, cardiomyopathy, mediastinal fibrosis, anomalous pulmonaryvenous drainage, pulmonary venoocclusive disease, collagen vasulardisease, congenital heart disease, HIV virus infection, drugs and toxinssuch as fenfluramines, congenital heart disease, pulmonary venoushypertension, chronic obstructive pulmonary disease, interstitial lungdisease, sleep-disordered breathing, alveolar hypoventilation disorder,chronic exposure to high altitude, neonatal lung disease,alveolar-capillary dysplasia, sickle cell disease, other coagulationdisorder, chronic thromboemboli, connective tissue disease, lupusincluding systemic and cutaneous lupus, schistosomiasis, sarcoidosis orpulmonary capillary hemangiomatosis.

Examples of asbestos-related disorders include, but not limited to,those described in U.S. publication no. 2005/0100529, published May 12,2005, which is incorporated herein by reference. Specific examplesinclude, but are not limited to, mesothelioma, asbestosis, malignantpleural effusion, benign exudative effusion, pleural plaques, pleuralcalcification, diffuse pleural thickening, rounded atelectasis, fibroticmasses, and lung cancer.

Examples of parasitic diseases include, but are not limited to, thosedescribed in U.S. publication no. 2006/0154880, published Jul. 13, 2006,which is incorporated herein by reference. Parasitic diseases includediseases and disorders caused by human intracellular parasites such as,but not limited to, P. falcifarium, P. ovale, P. vivax, P. malariae, L.donovari, L. infantum, L. aethiopica, L. major, L. tropica, L. mexicana,L. braziliensis, T Gondii, B. microti, B. divergens, B. coli, C. parvum,C. cayetanensis, E. histolytica, I. belli, S. mansonii, S. haematobium,Trypanosoma ssp., Toxoplasma ssp., and O. volvulus. Other diseases anddisorders caused by non-human intracellular parasites such as, but notlimited to, Babesia bovis, Babesia canis, Banesia Gibsoni, Besnoitiadarlingi, Cytauxzoon fells, Eimeria ssp., Hammondia ssp., and Theileriassp., are also encompassed. Specific examples include, but are notlimited to, malaria, babesiosis, trypanosomiasis, leishmaniasis,toxoplasmosis, meningoencephalitis, keratitis, amebiasis, giardiasis,cryptosporidiosis, isosporiasis, cyclosporiasis, microsporidiosis,ascariasis, trichuriasis, ancylostomiasis, strongyloidiasis,toxocariasis, trichinosis, lymphatic filariasis, onchocerciasis,filariasis, schistosomiasis, and dermatitis caused by animalschistosomes.

Examples of immunodeficiency disorders include, but are not limited to,those described in U.S. application Ser. No. 11/289,723, filed Nov. 30,2005. Specific examples include, but not limited to, adenosine deaminasedeficiency, antibody deficiency with normal or elevated Igs,ataxia-tenlangiectasia, bare lymphocyte syndrome, common variableimmunodeficiency, Ig deficiency with hyper-IgM, Ig heavy chaindeletions, IgA deficiency, immunodeficiency with thymoma, reticulardysgenesis, Nezelof syndrome, selective IgG subclass deficiency,transient hypogammaglobulinemia of infancy, Wistcott-Aldrich syndrome,X-linked agammaglobulinemia, X-linked severe combined immunodeficiency.

Examples of CNS disorders include, but are not limited to, thosedescribed in U.S. publication no. 2005/0143344, published Jun. 30, 2005,which is incorporated herein by reference. Specific examples include,but are not limited to, include, but are not limited to, AmyotrophicLateral Sclerosis, Alzheimer Disease, Parkinson Disease, Huntington'sDisease, Multiple Sclerosis other neuroimmunological disorders such asTourette Syndrome, delerium, or disturbances in consciousness that occurover a short period of time, and amnestic disorder, or discreet memoryimpairments that occur in the absence of other central nervous systemimpairments.

Examples of CNS injuries and related syndromes include, but are notlimited to, those described in U.S. publication no. 2006/0122228,published Jun. 8, 2006, which is incorporated herein by reference.Specific examples include, but are not limited to, CNS injury/damage andrelated syndromes, include, but are not limited to, primary braininjury, secondary brain injury, traumatic brain injury, focal braininjury, diffuse axonal injury, head injury, concussion, post-concussionsyndrome, cerebral contusion and laceration, subdural hematoma,epidermal hematoma, post-traumatic epilepsy, chronic vegetative state,complete SCI, incomplete SCI, acute SCI, subacute SCI, chronic SCI,central cord syndrome, Brown-Sequard syndrome, anterior cord syndrome,conus medullaris syndrome, cauda equina syndrome, neurogenic shock,spinal shock, altered level of consciousness, headache, nausea, emesis,memory loss, dizziness, diplopia, blurred vision, emotional lability;sleep disturbances, irritability, inability to concentrate, nervousness,behavioral impairment, cognitive deficit, and seizure.

Other disease or disorders include, but not limited to, viral, genetic,allergic, and autoimmune diseases. Specific examples include, but notlimited to, HIV, hepatitis, adult respiratory distress syndrome, boneresorption diseases, chronic pulmonary inflammatory diseases,dermatitis, cystic fibrosis, septic shock, sepsis, endotoxic shock,hemodynamic shock, sepsis syndrome, post ischemic reperfusion injury,meningitis, psoriasis, fibrotic disease, cachexia, graft versus hostdisease, graft rejection, auto-immune disease, rheumatoid spondylitis,Crohn's disease, ulcerative colitis, inflammatory-bowel disease,multiple sclerosis, systemic lupus erythrematosus, ENL in leprosy,radiation damage, cancer, asthma, or hyperoxic alveolar injury.

Examples of atherosclerosis and related conditions include, but are notlimited to, those disclosed in U.S. publication no. 2002/0054899,published May 9, 2002, which is incorporated herein by reference.Specific examples include, but are not limited to, all forms ofconditions involving atherosclerosis, including restenosis aftervascular intervention such as angioplasty, stenting, atherectomy andgrafting. All forms of vascular intervention are contemplated herein,including diseases of the cardiovascular and renal system, such as, butnot limited to, renal angioplasty, percutaneous coronary intervention(PCI), percutaneous transluminal coronary angioplasty (PTCA), carotidpercutaneous transluminal angioplasty (PTA), coronary by-pass grafting,angioplasty with stent implantation, peripheral percutaneoustransluminal intervention of the iliac, femoral or popliteal arteries,and surgical intervention using impregnated artificial grafts. Thefollowing chart provides a listing of the major systemic arteries thatmay be in need of treatment, all of which are contemplated herein:

Artery Body Areas Supplied Axillary Shoulder and axilla Brachial Upperarm Brachiocephalic Head, neck, and arm Celiac Divides into leftgastric, splenic, and hepatic arteries Common carotid Neck Common iliacDivides into external and internal iliac arteries Coronary Heart Deepfemoral Thigh Digital Fingers Dorsalis pedis Foot External carotid Neckand external head regions External iliac Femoral artery Femoral ThighGastric Stomach Hepatic Liver, gallbladder, pancreas, and duodenumInferior mesenteric Descending colon, rectum, and pelvic wall Internalcarotid Neck and internal head regions Internal iliac Rectum, urinarybladder, external genitalia, buttocks muscles, uterus and vagina Leftgastric Esophagus and stomach Middle sacral Sacrum Ovarian OvariesPalmar arch Hand Peroneal Calf Popliteal Knee Posterior tibial CalfPulmonary Lungs Radial Forearm Renal Kidney Splenic Stomach, pancreas,and spleen Subclavian Shoulder Superior mesenteric Pancreas, smallintestine, ascending and transverse colon Testicblar Testes UlnarForearm

Examples of dysfunctional sleep and related syndromes include, but arenot limited to, those disclosed in U.S. publication no. 2005/0222209A1,published Oct. 6, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, snoring, sleep apnea,insomnia, narcolepsy, restless leg syndrome, sleep terrors, sleepwalking sleep eating, and dysfunctional sleep associated with chronicneurological or inflammatory conditions. Chronic neurological orinflammatory conditions, include, but are not limited to, ComplexRegional Pain Syndrome, chronic low back pain, musculoskeletal pain,arthritis, radiculopathy, pain associated with cancer, fibromyalgia,chronic fatigue syndrome, visceral pain, bladder pain, chronicpancreatitis, neuropathies (diabetic, post-herpetic, traumatic orinflammatory), and neurodegenerative disorders such as Parkinson'sDisease, Alzheimer's Disease, amyotrophic lateral sclerosis, multiplesclerosis, Huntington's Disease, bradykinesia; muscle rigidity;parkinsonian tremor; parkinsonian gait; motion freezing; depression;defective long-term memory, Rubinstein-Taybi syndrome (RTS); dementia;postural instability; hypokinetic disorders; synuclein disorders;multiple system atrophies; striatonigral degeneration;olivopontocerebellar atrophy; Shy-Drager syndrome; motor neuron diseasewith parkinsonian features; Lewy body dementia; Tau pathology disorders;progressive supranuclear palsy; corticobasal degeneration;frontotemporal dementia; amyloid pathology disorders; mild cognitiveimpairment; Alzheimer disease with parkinsonism; Wilson disease;Hallervorden-Spatz disease; Chediak-Hagashi disease; SCA-3spinocerebellar ataxia; X-linked dystonia parkinsonism; prion disease;hyperkinetic disorders; chorea; ballismus; dystonia tremors; AmyotrophicLateral Sclerosis (ALS); CNS trauma and myoclonus.

Examples of hemoglobinopathy and related disorders include, but are notlimited to, those described in U.S. publication no. 2005/0143420A1,published Jun. 30, 2005, which is incorporated herein by reference.Specific examples include, but are not limited to, hemoglobinopathy,sickle cell anemia, and any other disorders related to thedifferentiation of CD34+ cells.

Examples of TNFα related disorders include, but are not limited to,those described in WO 98/03502 and WO 98/54170, both of which areincorporated herein in their entireties by reference. Specific examplesinclude, but are not limited to: endotoxemia or toxic shock syndrome;cachexia; adult respiratory distress syndrome; bone resorption diseasessuch as arthritis; hypercalcemia; Graft versus Host Reaction; cerebralmalaria; inflammation; tumor growth; chronic pulmonary inflammatorydiseases; reperfusion injury; myocardial infarction; stroke; circulatoryshock; rheumatoid arthritis; Crohn's disease; HIV infection and AIDS;other disorders such as rheumatoid arthritis, rheumatoid spondylitis,osteoarthritis, psoriatic arthritis and other arthritic conditions,septic shock, septic, endotoxic shock, graft versus host disease,wasting, Crohn's disease, ulcerative colitis, multiple sclerosis,systemic lupus erythromatosis, ENL in leprosy, HIV, AIDS, andopportunistic infections in AIDS; disorders such as septic shock,sepsis, endotoxic shock, hemodynamic shock and sepsis syndrome, postischemic reperfusion injury, malaria, mycobacterial infection,meningitis, psoriasis, congestive heart failure, fibrotic disease,cachexia, graft rejection, oncogenic or cancerous conditions, asthma,autoimmune disease, radiation damages, and hyperoxic alveolar injury;viral infections, such as those caused by the herpes viruses; viralconjunctivitis; or atopic dermatitis.

In other embodiments, the use of formulations, compositions or dosageforms provided herein in various immunological applications, inparticular, as vaccine adjuvants, particularly anticancer vaccineadjuvants, as disclosed in U.S. Publication No. 2007/0048327, publishedMar. 1, 2007, which is incorporated herein in its entirety by reference,is also encompassed. These embodiments also relate to the uses of thecompositions, formulations, or dosage forms provided herein incombination with vaccines to treat or prevent cancer or infectiousdiseases, and other various uses such as reduction or desensitization ofallergic reactions.

5. EXAMPLES

Embodiments provided herein may be more fully understood by reference tothe following examples. These examples are meant to be illustrative ofpharmaceutical compositions and dosage forms provided herein, but arenot in any way limiting.

5.1 Example 1: 0.5 mg Strength Pomolidomide Dosage Capsule

Table 1 illustrates a batch formulation and single dosage formulationfor a 0.5 mg strength pomolidomide single dose unit in a size #4capsule.

TABLE 1 Formulation for 0.5 mg strength pomolidomide capsule Percent ByQuantity Material Weight (mg/capsule) Pomolidomide ~1% 0.5* Starch 1500 56% 35    Sodium Stearyl Fumarate (PRUV) ~0.3%   0.16 Spray DriedMannitol (Mannogem EZ) remainder remainder Total 100.0%   62.5  *Denotesamount of pomolidomide that corresponds to the amount that provides thepotency of 0.5 mg of pomolidomide.

Pomolidomide was passed through a 35-mesh screen. Mannitol and starchwere each separately passed through a 25-mesh screen. Pomolidomide waspre-blended with a portion of mannitol and starch. The pre-blend wasmilled through a 0.039 inch screen. The remainder of the mannitol andstarch was also milled through a 0.039 inch screen. The pre-blend wasblended with the reminder of mannitol and starch. To this blend, sodiumfumarate, which was passed through a 60 mesh screen, was furtherblended. The final blend was encapsulated into a size #4 capsule.

5.2 Example 2: 1 mg Strength Pomolidomide Dosage Capsule

Table 2 illustrates a batch formulation and single dosage formulationfor a 1 mg strength pomolidomide single dose unit in a size #4 capsule.

TABLE 2 Formulation for 1 mg strength pomolidomide capsule Percent ByQuantity Material Weight (mg/capsule) Pomolidomide ~1%   1* Starch 1500 56%  70 Sodium Stearyl Fumarate (PRUV) ~0.3%      0.32 Spray DriedMannitol (Mannogem EZ) remainder remainder Total 100.0%   125 *Denotesamount of pomolidomide that corresponds to the amount that provides thepotency of 1 mg of pomolidomide.

Pomolidomide was passed through a 35-mesh screen. Mannitol and starchwere each separately passed through a 25-mesh screen. Pomolidomide waspre-blended with a portion of mannitol and starch. The pre-blend wasmilled through a 0.039 inch screen. The remainder of the mannitol andstarch was also milled through a 0.039 inch screen. The pre-blend wasblended with the reminder of mannitol and starch. To this blend, sodiumfumarate, which was passed through a 60 mesh screen, was furtherblended. The final blend was encapsulated into a size #4 capsule.

5.3 Example 3: 2 mg Strength Pomolidomide Dosage Capsule

Table 3 illustrates a batch formulation and single dosage formulationfor a 2 mg pomolidomide single dose unit in a size #2 capsule.

TABLE 3 Formulation for 2 mg strength pomolidomide capsule Percent ByQuantity Material Weight (mg/capsule) Pomolidomide ~1%   2* Starch 1500 56% 140 Sodium Stearyl Fumarate (PRUV) ~0.3%      0.64 Spray DriedMannitol (Mannogem EZ) remainder remainder Total 100.0%   250 *Denotesamount of pomolidomide that corresponds to the amount that provides thepotency of 2 mg of pomolidomide.

Pomolidomide was passed through a 35-mesh screen. Mannitol and starchwere each separately passed through a 25-mesh screen. Pomolidomide waspre-blended with a portion of mannitol and starch. The pre-blend wasmilled through a 0.039 inch screen. The remainder of the mannitol andstarch was also milled through a 0.039 inch screen. The pre-blend wasblended with the reminder of mannitol and starch. To this blend, sodiumfumarate, which was passed through a 60 mesh screen, was furtherblended. The final blend was encapsulated into a size #2 capsule.

5.4 Example 4: 3 mg Strength Pomolidomide Dosage Capsule

Table 4 illustrates a batch formulation and single dosage formulationfor a 0.5 mg strength pomolidomide single dose unit in a size #2capsule.

TABLE 4 Formulation for 3 mg strength pomolidomide capsule Percent ByQuantity Material Weight (mg/capsule) Pomolidomide ~1.6%   3* Starch1500  56%   100.8 Sodium Stearyl Fumarate (PRUV) ~0.3%    0.45 SprayDried Mannitol (Mannogem EZ) remainder remainder Total 100.0%  180*Denotes amount of pomolidomide that corresponds to the amount thatprovides the potency of 3 mg of pomolidomide.

Pomolidomide was passed through a 35-mesh screen. Mannitol and starchwere each separately passed through a 25-mesh screen. Pomolidomide waspre-blended with a portion of mannitol and starch. The pre-blend wasmilled through a 0.039 inch screen. The remainder of the mannitol andstarch was also milled through a 0.039 inch screen. The pre-blend wasblended with the reminder of mannitol and starch. To this blend, sodiumfumarate, which was passed through a 60 mesh screen, was furtherblended. The final blend was encapsulated into a size #2 capsule.

5.5 Example 5: 4 mg Strength Pomolidomide Dosage Capsule

Table 5 illustrates a batch formulation and single dosage formulationfor a 0.5 mg strength pomolidomide single dose unit in a size #2capsule.

TABLE 5 Formulation for 4 mg strength pomolidomide capsule Percent ByQuantity Material Weight (mg/capsule) Pomolidomide ~1.6%   4* Starch1500  56%   134.4 Sodium Stearyl Fumarate (PRUV) ~0.3%    0.6 SprayDried Mannitol (Mannogem EZ) remainder remainder Total 100.0%  240*Denotes amount of pomolidomide that corresponds to the amount thatprovides the potency of 4 mg of pomolidomide.

Pomolidomide was passed through a 35-mesh screen. Mannitol and starchwere each separately passed through a 25-mesh screen. Pomolidomide waspre-blended with a portion of mannitol and starch. The pre-blend wasmilled through a 0.039 inch screen. The remainder of the mannitol andstarch was also milled through a 0.039 inch screen. The pre-blend wasblended with the reminder of mannitol and starch. To this blend, sodiumfumarate, which was passed through a 60 mesh screen, was furtherblended. The final blend was encapsulated into a size #2 capsule.

5.6 Example 6: 5 mg Strength Pomolidomide Dosage Capsule

Table 6 illustrates a batch formulation and single dosage formulationfor a 5 mg pomolidomide single dose unit in a size #1 capsule.

TABLE 4 Formulation for 5 mg strength pomolidomide capsule Percent ByQuantity Material Weight (mg/capsule) Pomolidomide   ~2%   5* Starch1500   56% 168 Sodium Stearyl Fumarate (PRUV) ~0.3%    0.75 Spray DriedMannitol (Mannogem EZ) remainder remainder Total 100.0%  300 *Denotesamount of pomolidomide that corresponds to the amount that provides thepotency of 5 mg of pomolidomide.

Pomolidomide was passed through a 35-mesh screen. Mannitol and starchwere each separately passed through a 25-mesh screen. Pomolidomide waspre-blended with a portion of mannitol and starch. The pre-blend wasmilled through a 0.039 inch screen. The remainder of the mannitol andstarch was also milled through a 0.039 inch screen. The pre-blend wasblended with the reminder of mannitol and starch. To this blend, sodiumfumarate, which was passed through a 60 mesh screen, was furtherblended. The final blend was encapsulated into a size #1 capsule.

5.7 Example 7: Stability of Formulation

Accelerated stability was assessed under 40° C./75% RH, and levels ofimpurities over the time period of initial, 1 month, 3 months, and 6months were determined. Long term stability under 25° C./60% RH is alsoassessed during 0-24 months. For determination of the level ofimpurities, an HPLC gradient method was employed using the followingconditions:

Column: Zorbax SB-CN, 150 mm×4.6 mm id, 5 μm particle size

Temperature: Ambient

Mobile Phase: A: 10/90 methanol/0.1% trifluoroacetic acid

-   -   B: 80/20 methanol/0.1% trifluoroacetic acid

Time (min) % A % B Gradient Profile: 0 90 10 5 90 10 50 20 80 51 90 1060 90 10

Flow Rate: 1.0 mL/min

Injection Volume: 25 μL

Detection: UV, 240 nm

Run Time: 60 minutes.

From the experiments, it was observed that the impurities in theformulation provided herein stayed negligent throughout the time periodinvestigated. The performance characteristics of the dosage alsomaintained throughout the time period investigated. These results showthat the formulations provided herein have adequate stability forclinical and other uses.

While examples of certain particular embodiments are provided herein, itwill be apparent to those skilled in the art that various changes andmodifications may be made. Such modifications are also intended to fallwithin the scope of the appended claims.

What is claimed is:
 1. An oral dosage form in the form of a capsulewhich comprises: 1) pomalidomide at an amount of 0.1 to 3 weight percentof the total weight of the composition; 2) a binder or filler at anamount of 90 to 99 weight percent of total weight of the composition,wherein the binder or filler is a mixture of starch and mannitol; andwherein the ratio of mannitol:starch in the dosage form is from about1:1 to about 1:1.5.
 2. The oral dosage form of claim 1, whereinpomalidomide is present at an amount of 0.5 to 2 weight percent of totalweight of the composition.
 3. The oral dosage form of claim 1, whereinthe binder or filler is present at an amount of 95 to 99 weight percentof total weight of the composition.
 4. The oral dosage form of claim 1,wherein the starch is pregelatinized starch.
 5. The oral dosage form ofclaim 1, wherein the mannitol is spray dried mannitol.
 6. The oraldosage form of claim 1 further comprising a lubricant at an amount of0.01 to 1 weight percent of total weight of the composition.
 7. The oraldosage form of claim 6, wherein the lubricant is present at an amount of0.1 to 0.5 weight percent of total weight of the composition.
 8. Theoral dosage form of claim 7, wherein the lubricant is sodium stearylfumarate.